Method for treatment of nocturia

ABSTRACT

A method for treatment of nocturia by administering to a mammal, such as a human, in need of such treatment, a therapeutically effective amount of loxoprofen or a pharmacologically acceptable salt thereof.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation application of application Ser. No.11/471,340 filed Jun. 20, 2006 (abandoned), which is a continuationapplication of application Ser. No. 10/242,754 filed Sep. 13, 2002(abandoned).

FIELD OF THE INVENTION

The present invention relates to a preventive and/or therapeutictreatment of nocturia.

RELATED ART

Lower urinary tract symptoms (LUTS) are becoming a major health problemfor elderly people worldwide. Nocturia, a cause of insufficient sleepand thus impaired quality of life, is one of the main problems in LUTSalong with urinary incontinence and difficulty in urination. Theaetiology of nocturia is various and complex and obscure in manypatients, although LUTS, insomnia, nocturnal polyuria due tocardiovascular or renal hypofunction and disorders of the centralnervous system (CNS) may be among the causes (Resnick N. M., et al.,Campbell's Urology, 7th edn., Vol. 2 Chapt 31. Philadelphia: Saunders,1998: 1044-58).

The aeotiology of nocturia is still obscure in many patients, even inthose with BPH. In patients whose causes of nocturia are affirmable,such as those with LUTS, sleep disorder and nocturnal polyuria, nocturiamay be improved by effective treatment of these primary causes.Anticholinergic drugs, hypnotics, antidiuretic hormones, Chinese herbalmedicines and/or oestrogen for female patients are usually administeredfor nocturia in addition to treatments for their main diseases. However,in the inventor's experience, about one-half of such patients do notrespond well to these medications.

As for the effectiveness of nonsteroidal anti-inflammatory agents fortreatment of frequency of micturition, Al-Waili reported that in an opentrial indomethacin 100 mg suppository improved nocturia in all 15patients (Al-Waili, IRCS Med. Sci., 1986, 14, 322-3). In addition,Suzuki reported a patient whose nocturia was improved with indomethacinsuppository administered as antipyretics, and added a brief comment thatsome orally administered NSAIDs are also effective in nocturia (SuzukiS., Acta Urol. Jpn., 43, 402, 1997).

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide a medicament which iseffective for treatment of nocturia.

The inventor has surprisingly experienced that a patient who was beingtreated for BPH reported that his nocturia suddenly decreased from ausual of four voids to one void/night when he took a 60-mg tablet ofloxoprofen sodium (loxoprofen) prescribed for his shoulder pain beforesleeping. Based on the experience, the inventor conducted anon-randomized trial treatment with loxoprofen, a short-actingnonsteroidal anti-inflammatory drug (NSAID) prodrug usually prescribedat a dosage of 60 mg t.i.d. for the management of pair, in patientsbothered by nocturia. As a result, the inventor found that loxoprofenwas surprisingly effective for treatment of nocturia. The inventor alsofound that a class of nonsteroidal anti-inflammatory drugs are alsoeffective for treatment of nocturia. The invention was achieved on thebasis of these findings.

The present invention thus provides a medicament for preventive and/ortherapeutic treatment of nocturia, which comprises a nonsteroidalanti-inflamatory drug as an active ingredient.

The present invention also provides a method for preventive and/ortherapeutic treatment of nocturia, which comprises the step ofadministering to a mammal including a human in need of such treatment apreventively and/or therapeutically effective amount of a nonsteroidalanti-inflammatory drug, and a use of a nonsteroidal anti-inflammatorydrug for manufacture of the aforementioned medicament which comprisessaid nonsteroidal anti-inflammatory drug as an active ingredient.

Among a class of nonsteroidal anti-inflammatory drugs, a class ofphenylpropionic acid-type anti-inflammatory drugs are preferred, andloxoprofen is particularly preferred.

BEST MODE FOR CARRYING OUT THE INVENTION

Kinds of the nonsteroidal anti-inflamatory drugs as an active ingredientof the medicament of the present invention are not particularly limited.Any nonsteroidal anti-inflammatory drug can be used alone or incombination as the active ingredient of the medicament of the presentinvention. The term “nonsteroidal anti-inflammatory drug” used hereinmeans an anti-inflammatory drug which does not have a steroidal backbonestructure, and the scope of the nonsteroidal anti-inflammatory drugs isreadily apparent to one of ordinary skill in the art. Accordingly, theterm should not be construed any limiting sense and should be understoodin the broadest sense. In addition, the term “nonsteroidalanti-inflammatory drug” used herein encompasses a drug in a free form,as well as a pharmacologically acceptable salt thereof, a hydratethereof, or a solvate thereof. Any stereoisomer such as an opticalisomer or a diastereoisomer, or any mixture of the stereoisomer or aracemate of the nonsteroidal anti-inflammatory drug may be used. Anynovel nonsteroidal anti-inflammatory drugs as well as any clinicallyavailable nonsteroidal anti-inflammatory drugs may be used as activeingredients of the medicament of the present invention. Preferred classof nonsteroidal anti-inflammatory drugs include phenylpropionicacid-type anti-inflammatory drugs.

Examples of the nonsteroidal anti-inflammatory drugs include aspirin,lumiracoxib, etoricoxib, parecoxib, valdecoxib, tiracoxib, rofecoxib,celecoxib, darbufelone, dexketoprofen, aceclofenac, licofelone,bromfenac, pranoprofen, piroxicam, nimesulide, cizolirine, ketorolac,3-formylamino-7-methylsulfonylamino-6-phenoxy-4H-1-benzopyran-4-one,ibuprofen, meloxicam, lornoxicam, d-indobufen, mofezolac, nabumetone,amtolmetin, droxicam, pranoprofen, ketoprofen, tolfenamic acid,fenoprofen, flurbiprofen, suprofen, oxaprozin, loxoprofen, tenoxicam,zaltoprofen, ibuprofen, alminoprofen, and tiaprofenic acid, andpharmacological salt thereof, hydrate thereof, and solvate thereof.However, the nonsteroidal anti-inflammatory drugs are not limited tothese examples. Among them, loxoprofen and a pharmacological saltthereof is preferred, and loxoprofen sodium is more preferred.

The medicament of the present invention may be administered orally orparenterally to a patient with nocturia. When a clinically availablenonsteroidal anti-inflammatory drug is used as an active ingredient ofthe present invention, the available drug, per se, may be administeredto a patient with nocturia as the medicament of the present invention.Alternatively, a pharmaceutical composition may be administered to apatient which comprises at least one nonsteroidal anti-inflammatory drugas the active ingredient together with at least one pharmaceuticallyacceptable additive. The pharmaceutical composition can be prepared by amethod well knows to those skilled in the art. Examples of thepharmaceutical compositions suitable for oral administrations include,for example, tablets, capsules, powders, subtilized granules, granules,liquids, syrups and the like. Examples of the pharmaceuticalcompositions suitable for parenteral administrations include, forexample, injections, suppositories, inhalants, eye drops, nasal drops,ointments, creams, patches and the like.

The aforementioned pharmaceutical compositions may be prepared by theaddition of pharmaceutically acceptable additives to the activeingredient. Examples of pharmaceutically acceptable additives include,for example, excipients, disintegrators and disintegrating aids,binders, lubricants, coating agents, colorants, diluents, basematerials, dissolving agents and dissolving aids, isotonic agents, pHmodifiers, stabilizers, propellants, adhesives and the like.

A dose of the medicaments of the present invention is not particularlylimited, and the dose can suitably be selected depending on conditionssuch as, for example, route of administration, the age and body weightof a patient, symptoms, a purpose of preventive or therapeutic treatmentand the like. For example, for oral administrations, the medicament ofthe present invention may be administered in a dose of from 0.1 to 1,000mg per day, preferably mg to 100 mg for an adult. The medicament of thepresent invention may be administered once or several times a day, andpreferably, the medicament may be administered once before sleeping. Forexample, when loxoprofen is administered as the medicament of thepresent invention, a dose of 60 mg per day is preferred, and the dosemay preferably be administered once before sleeping. However, the doseand mode of administration is not limited to the above example.

EXAMPLE

The present invention win be explained more specify by way of examples.However, the scope of the present invention is not limited to theseexamples.

Patients and methods

One hundred forty one patients (136 men) aged 49 to 89 (mean 70.5) yearswith LUTS and =2 voids per night were enrolled in the study. Their maindiseases were BPH (n=93), prostate cancer (n=24) and neurogenic bladder(NB) (n=13); 11 had other diseases. The majority of patients had failedto respond to anticholinergic drugs, hypnotics and/or other medicationsfor nocturia prescribed in addition to their treatments for their maindiseases. Patients who had asthma gastrointestinal disorders, renaldysfunction end allergies to loxoprofen were excluded.

Patients took a single 60 mg loxoprofen tablet prior to sleeping atnight for 4 to 14 days initially concurrently with their treatments fortheir main diseases. Numbers of voids/night as reported by each patientwere evaluated and treatment outcome was assessed as either excellent(nocturia disappeared or decreased by =2 voids/night), improved(nocturia decreased by 1 void/night), unchanged or worsened (nocturiaincreased).

After the initial study, loxoprofen was administered at the patients'discretion; 101 continued loxoprofen therapy for =320 (mean 61) days.

Results

Changes in patients' symptoms were observed starting from the firstnight of therapy. Nocturia improved or disappeared in 72% of thepatients overall: excellent, improved, unchanged and worsened resultswere obtained in 36%, 36%, 24% and 4%, respectively (Table 1).

TABLE 1 Effects of loxoprofen in 141 patients with nocturia No. ofPatients Excellent Improved Unchanged Worsened Male, 135 49 (36%) 48(36%) 32 (24%) 6 (4%) Female, 6  2 (33%)  2 (33%)  2 (33%) — Total 14151 (36%) 50 (36%) 34 (24%) 6 (4%)

Patients whose nocturia improved generally reported noticeableimprovements in their quality of life through having sound sleep. Evenin the unchanged group, some patients reported sleeping better than theydid prior to treatment because the time to first voiding was delayed byseveral hours.

Loxoprofen's effects were analyzed on the basis of frequency of nocturiaat baseline (Table 2). The effects were better in patients whosebaseline frequency was >3 voids/night than in those with less-frequentnocturia: when the patients were divided into two groups, 56 with 2 to 3episodes of nocturia and 85 with more frequent nocturia, the excellentresponder rates were 21% and 46% in each, respectively (P=0.004,Fisher's exact test). The excellent responder rates slightly reducedwith increased age of patients: excellent responses were observed in 50%(4/8) of patients aged 49 to 59 years, 40% (17/43) in those aged 60 to69 years, 35% (23/65) in those aged 70to 79 years, and 28% (7/25) inthose aged 80 to 86 years.

TABLE 2 Effects of loxoprofen vs frequency of nocturia at baselineFrequency No. of at Baseline Patients Excellent Improved UnchangedWorsened 2 and 2-3 56 12* (21%) 23^(†) (41%) 19^(†) (34%) 2 (4%) 3-4 5928^(†) (47%) 18^(†) (31%) 10^(†) (17%) 3 (5%) 4-5 15 6 (40%) 6 (40%) 3(20%) — >5 11 5^(†) (45%) 3 (27%) 2 (18%) 1 (5%) Total 141 51 50 34 6*The percentage of patients showing excellent response significantlylower than in the other frequency-at-baseline groups (P = 0.004,Fisher's exact test). ^(†)Including one female patient.

Loxoprofen's effectiveness was also analyzed on the basis of thepatients' main diseases and related symptoms to nocturia (Table 3). Ofpatients with diseases of the prostate, the excellent and improved rateswere 39% and 34%, respectively, in 93 with BPH, who were mainly beingtreated with an alpha-blocker, and 29% and 33%, respectively, in 24 withprostate cancer, of whom 15 were receiving an LH-RH agonist. Loxoprofenwas remarkably effective in 13 patients with NB, in whom the excellentand improved response rates were 69% and 8%, respectively (P=0.036 vsresults obtained in patients with prostate diseases). Excellent responserates were also high in patients with insomnia (35%) and unary frequencywithout urge incontinence (44%). However, excellent rates were low inpatients with Gary frequency with urge incontinence (20%) and in thosewith nocturnal polyuria (14%).

TABLE 3 Efficacy of loxoprofen in nocturia by patients' main diseasesplus insomnia, urinary frequency, nocturnal polyuria or urgeincontinence Main Diseases and Symptoms No. of Patients ExcellentImproved Unchanged Worsened BPH 93 36 (39%) 32 (34%) 21 (23%) 4 (4%)Prostatodynia  5 1 (20%) 2 (40%) 1 (20%)  1 (20%) Prostate cancer 24 7(29%) 8 (33%) 8 (33%) 1 (4%) hormone therapy 15 5 3 6 1 post-radiation 4 1 3 — — post-prostatectomy*  5 1 2 2 — Neurogenic bladder  13^(†)9^(‡) (69%) 1^(¶) (8%) 2^(¶) (15%) 1 (8%) Interstitial cystitis   2^(¶) 2^(¶) Insomnia 20 7 (35%) 8 (40%) 4 (20%) 1 (5%) Urinary frequencywithout UUI  9 4^(¶) (44%) 2 (22%) 2^(¶) (22%)  1 (11%) with UUI 10 2(20%) 5^(†) (50%) 3^(¶) (30%) Nocturnal polyuria  7 1 (14%) 5 (71%) 1(14%) *Prostatectomy = radical prostatectomy. ^(†)Indicates two patientswere female. ^(‡)Percentage of patients showing excellent response issignificantly higher than in the other main disease groups (P = 0.036,Fisher's exact test). ^(¶)Indicates one patient was female. UUI, urgeincontinence.

Table 4 shows the effects of loxoprofen in patients who did not respondto previous treatments for nocturia concurrently with therapy for theirmain diseases. Since almost au of these patients bad bladder outletobstruction (BOO), anticholinergic drugs such as imipramine 10 mg oroxybutynin 2 mg had been administered prior to sleeping. In 108 patientswho did not respond to anticholinergic dregs, the excellent and improvedrates of loxoprofen were 44% and 38%, respectively. In 42 patients whodid not respond to hypnotics, the excellent and improved rates followinga loxoprofen therapy were 31% and 38%, respectively. However, excellenteffects were obtained only in one of nine patients who previouslyresponded or were refractory to antidiuretic hormone. Loxoprofen was aneffective treatment for nocturia in BPH patients who had undergonetransurethral resection of the prostate (TURP) or received previousthermotherapy: excellent responses were obtained in 44% of 18 patientswith nocturia appearing =2 years after TURF procedures were carried outand in 42% of 19 patients with BPH whose nocturia did not respond tothermotherapy.

TABLE 4 Efficacy of loxoprofen among non-responders to previoustreatments for nocturia Previous No. of Treatments Patients ExcellentImproved Unchanged Worsened Anticholinergics* 32 14 (44%) 12 (38%) 6(19%) 1 (3%) TCA^(†) 76 30 (39%) 28 (37%) 17 (22%)  4 (5%) Hypnotics 4213 (31%) 16 (38%) 11 (26%)  2 (5%) Antidiuretic hormone^(‡)non-responder  3  1 (33%) 2 (67%) responder  6  1 (17%)  4 (67%) 1 (17%)Post-TURP 18  8 (44%)  5 (27%) 4 (22%) 1 (6%) Post- 19  8 (42%)  5 (26%)6 (32%) thermotherapy^(‡) *Non-responders to oxybutynin hydrochloride 2mg, propiverine hydrochloride 10 mg and/or clenbuterol hydrochloride 40μg administered before sleeping. ^(†)Non-responders to imipraminehydrochloride 10 mg and/or amitriptyline hydrochloride administeredbefore sleeping. ‡Desmopressin nasal drop. ‡Patients who had nocturiafor approximately 2 years after TURP. TCA: tricyclic antidepressants.

After the evaluation, loxoprofen therapy was continued or not accordingto the patients' wishes (Table 5). Of 101 excellent and improvedpatients, 11 continued to take loxoprofen every night and 43 whennecessary. The improvement of nocturia lasted for several months evenafter discontinuation of therapy in 11 (10%) who discontinued loxoprofenafter 5 to 310 days' administration. In addition, in five patients inwhom loxoprofen's effectiveness reduce after continuous administrationthe effectiveness recovered with occasional administration followingwithdrawal for several weeks.

TABLE 5 Continuation and termination of loxoprofen administration afterthe trial treatment in patients with excellent and improved outcome a)Total Outcome Continued No. of Continued occasional Patientsadministration Administration Terminated Excellent 51  9 (18%) 26 (51%)16 (31%) (average days) (129) (95) (56) Improved 50 2 (4%) 17 (34%) 31(62%) (average days)  (60) (54) (20) Total 101 11 43 47 b) StatedReasons for Discontinuing Therapy No. of Patients with No. of Patientswith Excellent Response Improved Response (Mean No. of Prescription(Mean No. of Prescription Days) Days) Cured or stable 7 4 improvement(5-310 days/75 days) (5-42 days/26 days) Stopped 7 2 visiting clinic(11-56 days/27 days) (14, 19 days) Due to 1 9 adverse events (3-28days/10 days) No worry 7 about nocturia (5-21 days/11 days) Too many — 3drugs (7-28 days/15 days) Reduced 2 efficacy (35, 119 days) Others 1 4(underwent (30 days) (21-112 days/49 days) TURP etc) Total 16  31 

As shown in the above results, nocturia either improved or disappearedin 72% of patients. Considering that the majority of these patients didnot respond to treatments for their main diseases nor to anticholinergicdrugs and/or hypnotics, the effectiveness of loxoprofen is highlyencouraging. Anticholinergic drugs, which are most commonly given topatients with nocturia who do not respond to treatments for LUTS, arenot only limited to small doses for patients with BOO and NB, but alsofrequently cause constipation and dry mouth or thirst. In addition, manyelderly patients who receive hypnotics worry about habituation sideeffects.

One of the main merits of loxoprofen for the treatment of nocturia isthat it does not decrease voiding power even in patients with BOO anddoes not produce side effects such as dry mouth, constipation andhabituation. In addition, improvements of nocturia lasted in somepatients even after the discontinuation of loxoprofen, and in somepatients in whom the effects were reduced during continuousadministration, the benefits were recovered after switching tooccasional administration following withdrawal for several weeks. Theseresults clearly indicate that loxoprofen is highly effective for thetreatment of nocturia.

1. A method for the treatment of nocturia which consists ofadministering to a mammal in need of such treatment a therapeuticallyeffective amount of a nonsteroidal anti-inflammatory drug consisting ofloxoprofen or a pharmacologically acceptable salt thereof.
 2. The methodaccording to claim 1, wherein loxoprofen or a pharmacologicallyacceptable salt thereof is loxoprofen.
 3. The method according to claim1, wherein the mammal is a human.
 4. The method according to claim 2,wherein the mammal is a human.
 5. The method according to claim 1,wherein the mammal is a human whose frequency of nocturia at baseline is3 or more voids/night and the number of voids per night is reduced by 1or more times in more than 77% of the humans after the treatment, andwherein the administration is once daily.
 6. The method according toclaim 1, wherein the mammal is a human whose frequency of nocturia atbaseline is 3 to 5 voids/night and the number of voids per night isreduced by 1 or more times in more than 78% of the humans after thetreatment, and wherein the administration is once daily.
 7. A method forthe treatment of nocturia which consists of administering to a mammal inneed of such treatment a therapeutically effective amount of anonsteroidal anti-inflammatory drug consisting of a pharmacologicallyacceptable sodium salt of loxoprofen.
 8. The method according to claim7, wherein the mammal is a human.
 9. The method according to claim 7,wherein the mammal is a human whose frequency of nocturia at baseline is3 or more voids/night and the number of voids per night is reduced by 1or more times in more than 77% of the humans after the treatment, andwherein the administration is once daily.
 10. The method according toclaim 7, wherein the mammal is a human whose frequency of nocturia atbaseline is 3 to 5 voids/night and the number of voids per night isreduced by 1 or more times in more than 78% of the humans after thetreatment, and wherein the administration is once daily.